Regenerative Rehabilitation — Towards the Optimization of Rehabilitation Strategies to Improve the Efficacy of Regenerative Therapies for the Treatment of Volumetric Muscle Loss Injury

Project Details


Alignment with Department of Defense (DoD) Gap/Priority Areas: The proposed work is directly in line with the overarching vision of the DoD’s Medical Research Program, specifically the portfolio of Joint Programm Committee 8/Clinical and Rehabilitative Medicine Research Program. Specifically, the Regenerative Rehabilitation proposal described herein addresses the following DoD focus/gap areas:• Tissue Regeneration: Evaluate advanced regenerative medicine therapeutics for restoration of traumatically injured extremity tissues.• Surgical Techniques and Outcomes: Evaluate optimal surgical treatment strategies, tools, and delivery parameters in Volumetric Muscle Loss (VML) to improve functional outcomes for immediate return to duty/work for Service members (SMs) and other individuals who have sustained orthopaedic injuries.• Rehabilitation Techniques and Outcomes: Evaluate optimal rehabilitation treatment strategies, tools, and delivery parameters to improve functional outcomes for early return to duty/work for SMs and other individuals who have sustained orthopaedic injuries.Background:• Traumatic extremity injuries are the hallmark of recent military conflict.• The surgical and rehabilitative care for patients with extremity trauma has been pioneered within the US Military Health System.• The volumetric loss of skeletal muscle is a limb-associated morbidity that persists despite what may be considered a surgical success for either the amputated or reconstructed limb.• The current standard of care for VML injury for active duty SMs is physical therapy.• Current regenerative paradigms for VML injury have yielded promising preclinical results, but require augmentation to achieve a clinically important difference.• The magnitude of bulk tissue loss associated with VML is irrecoverable in mammals, leading to a chronic reduction in total muscle fiber number and gross fibrosis within the muscle compartment that results in a reduction in functional capacity.• The natural history of VML injury involves heightened and prolonged compartmental inflammation that drives the fibrotic tissue response.• Inhibition of fibroblast to myofibroblast conversion following VML injury may establish a compliant environment amenable to tissue reconstruction via physical therapy and regenerative therapies.• Regenerative and Rehabilitative Medicine: A Necessary Synergy for Functional Recovery from VML Injury.Overarching Objective: An overarching objective of our research program is to develop individualized, patient-specific (i.e., personalized medicine) Regenerative Rehabilitation based therapies capable of providing the highest level of functional performance and optimal quality of life for SMs and Veterans with traumatic extremity injuries. However, before this can be achieved, numerous aspects of those injuries, including VML injuries, require further investigation. Thus, preclinical Regenerative Rehabilitation themed studies that seek to elucidate these key questions, particularly those focused on VML injuries, are crucial to understanding the fundamental mechanisms related to the interplay between mechanobiology and tissue regeneration.Goal/Hypothesis: The primary goal of this study is to develop a synergistic Regenerative Rehabilitation treatment program that facilitates optimal functional outcomes following VML injury. The proposed work will test the hypothesis that optimization of timing of a gold standard rehabilitation therapy will improve the efficacy of a comprehensive regenerative medicine treatment strategy and thus facilitate improved skeletal muscle form and function compared to either the rehabilitation or regenerative interventions in isolation.Specific Aims: The specific aims of this study are:SAI: Evaluate the Effects of Dosing and Scheduling of ITA for Reduction of Fibrotic Tissue Deposition in a Rat Hindlimb Model of Volumetric Muscle Loss.SAII: Evaluate Regenerative Outcomes associated with Administration of ITA in Concert with Regenerative Medicine Therapies in a Rat Hindlimb Model of Volumetric Muscle Loss.SAIII: Optimization of a Regenerative Rehabilitation Program to Improve Functional Outcomes in a Rat Hindlimb Model of Volumetric Muscle LossMilitary Benefit: Traumatic Extremity injuries are the most common wounds for Wounded Warriors and are responsible for most of the hospital costs and disability payments associated with combat-related injuries. This proposal will evaluate combining antifibrotic, regenerative, and rehabilitative approaches to improve functional outcomes. This research represents a significant advancement in the understanding of this underrepresented component of care for severe extremity trauma. If successful, the technology developed through these efforts is primed to transition quickly into clinical practice and has the potential to transform the care and quality of life of Wounded Warriors.

Effective start/end date1/09/1931/08/22


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